Pharmacoproteomic characterisation of human colon and rectal cancer

Molecular Systems Biology
Martin FrejnoBernhard Kuster

Abstract

Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome-guided pre-clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials.

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Citations

Aug 15, 2018·Molecular Systems Biology·Christina LudwigRuedi Aebersold
May 3, 2019·Molecular Systems Biology·Srivamshi PittalaChris Bailey-Kellogg
Jul 28, 2019·Bioinformatics·Leonard SchmiesterDaniel Weindl
Jul 21, 2020·Nature Communications·Martin FrejnoBernhard Kuster
Oct 31, 2019·Nucleic Acids Research·Patroklos SamarasMathias Wilhelm
Jan 25, 2020·Cell·David P NusinowSteven P Gygi
Nov 14, 2020·International Journal of Cancer. Journal International Du Cancer·Tianzuo ZhanMichael Boutros
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Apr 17, 2021·Expert Review of Proteomics·Daniela BraconiAnnalisa Santucci
Apr 25, 2021·Scientific Data·Andrew F JarnuczakJuan Antonio Vizcaíno

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Methods Mentioned

BETA
histone acetylation
pulldowns
protein assay
electrophoresis
acetylation

Software Mentioned

Kinobeads
ComBat
QUASAR
Columbus
MComBat
MaxQuant
SAM
MetaCore
R scripts
R

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